K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Somatic mutations in K-Ras are common in cancer, linked to poor treatment outcomes.
• Directly targeting K-Ras is challenging due to its high affinity for GTP/GDP and lack of known allosteric sites.
• Oncogenic K-Ras mutations impair GTP hydrolysis, increasing the proportion of active GTP-bound Ras.

Purpose of the Study:

• To develop small molecules that selectively target the oncogenic K-Ras(G12C) mutant.
• To identify and validate a novel allosteric binding site on K-Ras(G12C).

Main Methods:

• Development of irreversible small molecule inhibitors specific to K-Ras(G12C).
• Crystallographic studies to elucidate the binding mechanism and identify new pockets.
• Biochemical assays to assess nucleotide binding and effector interactions.

Main Results:

• Irreversible inhibitors were developed that bind specifically to K-Ras(G12C) via the mutant cysteine.
• Crystallography revealed a novel binding pocket beneath the switch-II region.
• Inhibitor binding disrupts switch-I and switch-II, shifting nucleotide preference from GTP to GDP and impairing Raf binding.

Conclusions:

• A new, mutant-specific allosteric site on K-Ras(G12C) has been identified and validated.
• These findings provide a structure-based strategy for developing targeted therapies against K-Ras(G12C) mutant cancers.